Chromosomal instability as a driver of non-small cell lung cancer immune evasion and brain metastasis

染色体不稳定性是非小细胞肺癌免疫逃避和脑转移的驱动因素

• 批准号: 10679841
• 负责人: Lindsay Anne Caprio
• 金额: $ 4.77万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679841
• 关键词: Adenosine; Behavior; Biology; Brain; CRISPR/Cas technology; Cancer Biology; Cancer Etiology; Cancer Patient; Cell Line; Cells; Cephalic; Cessation of life; Characteristics; Chromosomal Instability; Chromosome Arm; Chromosome Segregation; Chronic; Coupled; Cytosol; DNA; Data Set; Databases; Development; Disease; Drug resistance; Environment; Evolution; Failure; Future; GENIE; Generations; Genetic; Genetic Engineering; Goals; Human; Image; Immune Evasion; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Situ; In Vitro; Injections; Interferon Type I; Investigation; KRASG12D; Label; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Medical center; Mentors; Metastatic malignant neoplasm to brain; Methods; Mitosis; Modeling; Molecular; Mus; Mutate; Mutation; NF-kappa B; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Output; Pathway interactions; Phosphotransferases; Physicians; Primary Neoplasm; Process; Production; Proteins; Recycling; Research; Resistance; Risk; Role; Rupture; STK11 gene; Scientist; Signal Transduction; Stimulator of Interferon Genes; Surface; System; TP53 gene; Tail; Testing; The Cancer Genome Atlas; Tissues; Tumor Escape; Tumor Promotion; Tumor Subtype; Universities; Up-Regulation; Validation; Veins; Work; blood-brain barrier permeabilization; cancer cell; cancer type; career; chromosome loss; combinatorial; ds-DNA; ecto-nucleotidase; experimental study; genome sequencing; genomic data; immune checkpoint blockade; immunoregulation; in vivo; melanoma; micronucleus; mouse model; multimodality; mutant; neoplastic cell; refractory cancer; response; spatiotemporal; therapeutic development; transcriptomics; tumor; tumor behavior; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Brain metastasis (BM) frequently arises from non-small cell lung cancer (NSCLC) and represents the most common cause of cancer related death in the US, yet our understanding of BM biology is rudimentary. Our group has recently identified excessive chromosomal instability (CIN) as a hallmark of BM19. In in vitro studies, in addition to validation in multiple independent NSCLC patient datasets (TCGA, GENIE, CCLE, and CPTAC) detailed in this proposal, we have identified CIN as a hallmark of NSCLCs harboring mutations in STK11 (encoding LKB1). LKB1-deficient NSCLCs are an aggressive tumor subtype associated with increased risk of BM and immunotherapy resistance, and thus serves as a relevant archetypical disease that may broadly inform the role of CIN in BM biology and cancer immune evasion. CIN arises from failures in correct chromosome segregation during mitosis, leading to perpetual gains and losses of chromosome arms and the creation of rupture-prone micronuclei. Upon rupture, these micronuclei expose DNA to the cytosol, activating cGAS-STING signaling. This would seemingly present a conundrum for CINhigh cancers, as prototypical outputs of cGAS- STING activation promote anti-tumor type I interferon (IFN) responses. However, it has been recently shown that chronic cGAS-STING signaling characteristic of CINhigh tumors promotes metastatic non-canonical NF-kB output, in addition to immune-evasive adenosine generation in the tumor microenvironment, the latter accomplished through adaptive increases in cGAMP export and upregulation of surface ectonucleotidases ENPP1 and NT5E. In addition to its ability to promote immunosuppression, adenosine also permeabilizes the blood brain barrier and thus may potentially mechanistically link BM to CIN. This proposal seeks to understand how cancer cell adaptations to CIN enable BM and immune evasion, namely through investigation of tonic activation of cGAS-STING signaling. In Aim 1, I propose to delineate the respective contributions of CIN and LKB1 loss per se to metastatic behavior and immunotherapy resistance in vivo. In Aim 2, I will perform spatio- temporal resolved in vivo studies to delineate CIN-intrinsic (i.e., STING signaling) and -extrinsic (e.g. adenosine generation) interactions that enable immune evasion and BM. Through generation of genetic perturbations in LKB1-deficient and WT models, I will investigate whether chronic cGAMP-triggered STING recycling is a hallmark of CINhigh, LKB1-deficient NSCLC that favors immune-evasive tumor behavior and establishment of BM. Together, these aims offer unparalleled study of interactions critical for the establishment of the brain metastatic niche and will pave the way for therapeutic development of malignant, treatment-resistant CINhigh tumors. With the guidance from exceptional mentors and collaborators and access to the unparalleled scientific research environment at Columbia University Irving Medical Center, this project will prepare me for a successful career as a physician-scientist in the field of cancer biology.

项目摘要/摘要 脑转移瘤(BM)多见于非小细胞肺癌(NSCLC)，以非小细胞肺癌最常见 在美国，癌症相关死亡的常见原因，但我们对BM生物学的理解是初级的。我们的团队 最近发现过度的染色体不稳定(CIN)是BM19的一个特征。在体外研究中， 除了在多个独立的NSCLC患者数据集(TCGA、GENIE、CCLE和CPTAC)中进行验证外 在这项建议中，我们已经确定CIN是含有STK11突变的非小细胞肺癌的标志。 (编码LKB1)。LKB1缺陷的NSCLC是一种侵袭性肿瘤亚型，与 BM和免疫治疗耐药，因此作为一种相关的典型疾病，可能会广泛地 CIN在骨髓生物学和肿瘤免疫逃逸中的作用CIN源于正确的染色体失败 有丝分裂过程中的分离，导致染色体臂的永久获得和丢失，以及 易破裂的微核。一旦破裂，这些微核将DNA暴露在胞浆中，激活cGAS-STING 发信号。这似乎给CINHigh癌症带来了一个难题，因为cGAS的原型产物- STING激活可促进抗肿瘤I型干扰素(干扰素)反应。然而，它最近被展示出来 CIN高表达肿瘤的慢性cGAS-STING信号特征促进非典型性核因子-kB转移 输出，除了在肿瘤微环境中免疫逃避腺苷的产生，后者 通过适应性增加cGAMP出口和上调表面胞外核苷酸酶来实现 ENPP1和NT5E。除了促进免疫抑制的能力外，腺苷还能渗透 血脑屏障，因此可能潜在地将BM与CIN机械地联系起来。这项提议试图理解 癌细胞对CIN的适应性如何使BM和免疫逃逸，即通过研究强的松 CGAS-STING信号的激活。在目标1中，我建议说明CIN和CIN各自的贡献 LKB1本身的丢失与体内转移行为和免疫治疗耐受有关。在目标2中，我将表演空间- 时间分辨的体内研究，以描绘CIN内在的(即，刺痛信号)和非外在的(例如，腺苷 代)相互作用，实现免疫逃避和BM。通过遗传扰动的产生 LKB1缺乏和WT模型，我将调查慢性cGAMP触发的刺伤回收是否是一种 CINHigh，LKB1缺陷的NSCLC的标志，有利于免疫逃逸肿瘤行为和BM的建立。 总而言之，这些目标提供了对相互作用的无与伦比的研究，这些相互作用对于建立脑转移瘤至关重要 并将为恶性、耐药CINHigh肿瘤的治疗开发铺平道路。使用 来自杰出导师和合作者的指导以及对无与伦比的科学研究的访问 哥伦比亚大学欧文医学中心的环境，这个项目将为我的职业生涯做好准备 作为癌症生物学领域的内科科学家。